amide: N- vs O-alkylation
Gabriel Tojo
>
>
> No, the problem is he has a primary amine, he makes the aminde, and
> then he alkylates the nitrogen. Leave off the amide and go for direct
> monomethylation. The best protecting group is no protecting group.
>
> Hell, make the formamide and reduce it.
You are right, I overlooked the first part of the post.
This is a problem of monomethylation of a primary amine. Direct use of MeI fails
because of polyalkylation. Polyalkylation could be prevented with other alkyl groups,
but a methyl is too small and reactive to stop the reaction on the first alkylation.
In this case, the two commonest solution are:
1- Reduction of the formamide, as you suggest. Some references are AcOCHO and
BH3.Me2S, JOC, 9414, 98 and 5946, 99; HCO2H/Ac2O and BH3.THF, JACS, 1841, 96.
2- Boc protection, methylation and deprotection: Tetrahedron, 1111, 2000; JOC, 2711,
99; JACS, 7778, 99.
Acetylation, methylation and deprotection is feasible, although the demethylation
demands much harsher conditions than Boc deprotection, with is normally done with mild
TFA.
The reduction of a formamide involves the use of dangerous and expensive hydrides.
Steve´s procedure may have some virtues.
Best regards.
--
Gabriel Tojo
Internet Scientific Consultant in Organic Synthesis
Profesor Titular de Química Orgánica
Royal University of Santiago de Compostela
SPAIN
--
Paul J. Franklin (moderator - sci.chem.organic.synthesis)
http://chemistry.gsu.edu/post_docs/koen/wnewshp.html
Georgia State University <che...@panther.gsu.edu>
Atlanta, GA
Bimb
As I understand, the limiting factor for this reaction is the poor
solubility of anorganic Li-salts in nonpolar organic solvents. In this
regard, I suppose one eq. of n-BuLi would be an interesting option. In my
case, unfortunately, dioxane is the least polar solvent that reasonably
dissolves my product.
You're right about the concentration. The second time I carried out this
reaction I prepared the amide in another way under high dilution (and did an
immediate alkylation afterwards). The reaction time was indeed almost twice
as long.
When you say: "Yes, it is a problem of hard versus soft alkylation
conditions. Hard promotes O-alkylation and soft promotes N-alkylation.", I
suppose that you talk about the nature of the electrophile (otherwise soft
Cs+ would be the better cation). I will try to add some iodide in this
regard.
Many thanks,
Frederik
Gabriel Tojo <qoga...@usc.es> wrote in message
news:8jabst$m...@panther.Gsu.EDU...
> Uncle Al wrote:
> >
> > Steve MacB wrote:
> > >
> > > This is how I do it,
> > > First make the acetanilide (amine + Ac2O, 2eq), quench into water and
dry
> > > well. Dissolve product in THF and add a solution of KtBuOH (1.1eq) in
THF
> > > (Mildly exothermic), then slowly add methyl Iodide [or other alkyl
iodide as
> > > required] (1.1eq) then bring to reflux. Allow to cool and quench into
water,
> > > extract and concentrate (may need distillation). Deacetylate in conc
HCl
> > > 10eq at reflux for a couple of hours. Basify with dil NaOH and
extract.
> > > Concentrate and distill/ReXT as neccessary. A lot of steps I know, but
> > > overall yields of 80% at >98% purity can be achieved. HTH
> >
> > If you want to make the monomethylated amine, HCHO and BH3CN-, then
> > chromatograph on basic alumina.
>
> The problem is not the monoalkylation of an amide, but the selective
N-alkylation
> versus O-Alkylation.
>
> Yes, it is a problem of hard versus soft alkylation conditions. Hard
promotes
> O-alkylation and soft promotes N-alkylation.
>
> Polar solvents and bulky cations promote O-alkylation, while apolar
solvents and
> small cation promote O-alkylations.
> Precisely those conditions promoting O-alkylation are the ones that allow
quicker
> reactions.
> For maximum proportion of N-alkylation you would need something like
LiH/benzene, but
> the reaction would be extremely slow. Normally, regarding amides, a
compromise is
> reached with something like NaH/DMF or NaH/THF (JACS, 311, 97;
Tetrahedron, 1153,
> 98;.JOC, 6283, 99)
> On the other hand, the tendency to O-alkylation varies very much with the
amide
> structure, and many amides are efficiently N-alkylated even with
Cs2CO3/DMF, which
> one would think that should promote O-alkylation (Tetrahedron, 1175, 92;
JOC, 3986,
> 98)
> Your case is an intermediate one, and not very difficult. You have
N-alkylation with
> Cs2CO3/dioxane, in spite of the use of Cs+. You have N-alquilation with
NaH and an
> unknown solvent and N plus O-alkylation with polar acetone.
> Remember that the speed is proportional to the product of the
concentration of the
> reagents. If you double the concentration, the velocity would increase
4-fold.
> I would try with Cs2CO3/dioxane, using the minimum amount of dioxane that
solubility
> allows.
> Best regards.
> --
> Gabriel Tojo
--